Certain n-(aminophenoxy pentyl) sulfonamide or saccharine compounds and higher homologues



United States Patent This invention is for improvements in or relating to amines and to processes for their preparation and has for its object the provision of new, therapeutically active substances. This application is a continuation-in-part of applicants Serial No. 503,820, filed April 25, 1955, now abandoned.

The new substances of the" present invention are the N-p-amino-phenoxyalkyl-amides represented by the general formula:

R1R2NO(OH2)"R3 wherein R and R are each selected from hydrogen, lower alkyl and lower hydroxyalkyl, n is an integer from 5 to 9 and R is a group selected from m'ethanesulphonamido (-NHSO CH benzenesulphonamido V (NHSO C H and o-sulphobenzimido The term lower is used to denote alkyl groups of l to 2 carbon atoms.

The new substances may be prepared and used in the form of their acid addition salts, and such salts are within the scope of the present invention. Also within the scope of the present invention are amine derivatives such as those commonly used in pharmaceutical practice, such as formaldehyde bisulphite addition products.

The said new compounds have been found to possess valuable therapeutic properties, particularly in the treatment of bilharziasis. The said new compounds may be prepared by the condensation of a compound of the formula XQOA with a compound of the formula Z Y wherein X represents a tertiary amino group or an atom or group capable of being replaced by or converted into a primary, second! ary or tertiary amino group, Y represents the group R or an atom (e. g. a halogen atom) or group which can be replaced by or converted into the group R and Z and Z are atoms or groups capable of reacting together to produce the linkage (CH or a corresponding less saturated hydrocarbon linkage. If necessary the groups X and Y are then converted into the groups NR R and R respectively and, also if necessary, a said less saturated hydrocarbon linkage is reduced to form the group Among the groups which may be represented by X are:

(a) .Groups convertible into primary amino groups: acylamido, carbonamido, nitro, nitroso, alkoxycarbonylamido, an il and arylazo groups; 7

(b) Groups convertible into secondary amino groups:

ice

2 anil, alkoxycarbonylamido and acylamido groups (by reduction) and acylalkylamido groups (by hydrolysis); and

(c) Tertiary amino groups or groups convertible into tertiary amino groups on the form of quaternary ammonium groups (by pyrolysis) and acylalkylamido groups (by reduction).

Examples of groups which may be represented by Y are:

(a) Acetamido, benzamido, diacetamido, succinimido, phthalimido and benzenesulphonamido groups. One acylamido group may be converted into another by hydrolysis (or in the case of the phthalimido group by treatment with hydrazine) and subsequent acylation (including sulphonylation); and

(b) A nitro group which may be converted by reduc tion and subsequent acylation (includingsulphonylation) Examples ofgroups which may be represented by Z and Z are hydrogen and alkali metal atoms and the groups Q(CH ),,whe're Q represents the radical of a reactive ester such as a methanesulphonate radical of a halogen atom.

In addition, compounds of the foregoing general formula and containing primary or secondary amino groups may be converted into products containing more highly substituted amino groups by known methods. For example, a product containing a primary amino group may be reacted with an alkylating agent or alkylene oxide.

It is not, of course, necessary that X when not identical to NR R shall be convertible or replaceable thereby in a single step. Thus, if X represents a hydrogen atom the resulting condensation product may first be nitrated (by means of nitric acid) Whereafter the nitro group is reduced to amino and, if required, the resultant amine is alkylated. The same considerations apply to the radical Y.

It will be apparent to those skilled in the art that the particular reaction and the sequence of reactions will in many cases be determined by the values desired for R R and R and by the appropriate value selected for the groups X and Y. The methods employed for carrying out the various steps in the processes of the present invention are known per se and have been previously described in the literature.

The present invention includes within its scope pharmaceutical preparations containing one or more compounds of the aforesaid general formula or an acid addition salt or other simple derivative thereof for use in the treatment of bilharziasis in which the active material is associated with a pharmaceutical carrier which may be either a solid material or liquid. The compositions may take the form of elixirs or of tablets, powders, capsules, or other dosage forms which are particularly suitable for oral ingestion. Liquid diluents are employed in sterile condition for parenteral use, that is, by injection. Such a medium may be a sterile liquid such as water. compositions of the invention may take the form of active' material, admixed with solid diluents and/or excipients such as starch, lactose, talc, stearic acid, magnesium stearate, gums or the like. Any of the tabletting materials used in pharmaceutical practice may be employed where there is no possibility of incompatibility with the active therapeutic agent. Alternatively, the active therapeutic agent may, with or without its adjuvant material, beplaced in the usual capsule of resorbable material such as the usual gelatine capsule and administered in that form.

The therapeutic value of the compounds of the invention may be shown bytheir activity against Schistosoma mansoni and in the following test data compounds according to the present invention are shown in comparison with l-m-diethylaminophenoxy-Z-methanesulphonamidoethane (United States Patent No. 2,592,364) to show the criticality of the various classes of compounds with which the present invention is concerned.

TEST PROCEDURE Mice were infected intraperitoneally with cercariae of 5 S. mansoni (80-120 per mouse). After 7-8 weeks they were'treated daily for four days by mouth with an aqueous solution or suspension of the drugs. The mice were killed and examined 7-14 days after the end of treatment Example I A solution of S-p-nitrophenoxypentyl bromide (3.6 g.)

and compared with untreated controls from the same 10 and soluble saccharine (4.0 g.) in ethanol (25 ml.) was batch of infected animals. If no living worms were refluxed for 3 hours, cooled and filtered. The solid prodfound in a treated mouse it was considered to be cured. not was washed with water and crystallised from ethanol,

yielding 1-p-nitrophenoxy-5(2:3-dihydro-1:l :3 trioxo- COMPQUNDS TESTED benzoisothiazol-Z-yl)-pentane M. P. 125-127" 0. Reduc- The compound tion of this nitro compound (19.6 g.) with hydrogen over 2% of platinum oxide in ethanol (300 ml.) at 74 C. HzNO(CH2)rNH-SO (260 lb. per sq. in.) gave l-p-aminophenoxy-S-(Z:3-dihydro-1 1 :3-trioxobenzosiothiazol-2-yl)-pentane [N-5 pherein identified as A. V aminophenoxypentyl)saccharine] M. P. 114-115 C. The compound (Compound B above.)

0 Example ll Methanesulphonyl chloride (17.2 g.) was added to a HiN Q C(CHm solution of S-amino-l-p-nitrophenoxypentane (33.6 g.) so, in pyridine (100. ml.) and the mixture was kept overherein identified as night and then diluted with water and filtered. Crystal- The Compound lisatlon of the product from ethanol (using charcoal) gave l-p-nitrophenoxy 5 methanesulphonamidopentane HZMQAWHWNESOFCHJ M. P. 94-96 0. Reduction of this compound (20.6 g.) I 20 by hydrogen over Raney nickel in ethanol (300 ml.) at hcrein identified as C 74 C./74 lb. per sq. in. gave l-p-aminophenoxy-S- The compound methanesulphonamidopentane M. P. 122-123 C. (Compound C above.) Similarly prepared were: HrN (o z)s-'NH-soz 1-p-nitrophenoxy-S-benzenesulphonamidopentane M. P. 6768 C. which when reduced by the method of Exherein identified as D. ample I gave 1-p-aminophenoxy-S-benzenesulphonamido- The compound pentane M. P. 124-126 C. (compound A above).

CH3 1-p-nitrophenoxy-8-benzenesulphonamidooctane, M. P. 73-75 C. which on reduction yields l-p-aminophenoxy- 4o 8-benzene-sulphonamidooctane M. P. 121-122" C. Com- CH3 pound D above.) herein identified as E. Example The cornPound A mixture of l-p-aminophenoxy-S-benzenesulphonamidopentane (1.4 g.), sodium bicarbonate (0.7 g.), O (OH91NH SO1 CH3 methyl iodide (5 ml.) and ethanol (10 ml.) was refluxed for 20-hours, cooled and filtered. The product was re- NWIHE) crystallised from water, yielding the quaternary iodide herein identified as F. M. P. 183-185 C. Pyrolysis of this iodide at 20 mm.

RESULTS OBTAINED Acute nral Daily thera- Average Compound LDsu, peutie dose, Total No. Total N0. N0. of Standard mgJg. mgJg. (oral) of mice of worms worms error permouse 5:2 1% 1% if? 32093 11 39 3.8 $0.9 11 2 1% 7i 21% $1 3 1 10 190 10.0 $4.4 0.0 0. 25 9 20 2.2 $0.4 11 104 9.5 $3.9 4.0 0.4 5 1 0.2 $0.2 7 71- 11.0 $4.2 4.0 1.0 12 0 0.0 17 180 10.6 $3.1 2. 0 0. 4 13 104 s. 0 $1. 4 15 103 6.8 $0.9

pressure and recrystallisation of the residue from ether yielded 1-p-dimethylaminophenoxy-5benzenesulphonamidopentane M. P. 7072 C. (Compound E above.)

Example IV N-acetyl-p-methylaminophenol (66 g.) and 5-phthalimidopentyl bromide (118.3 g.) were added to a solution of sodium (9.2 g.) in ethanol (400 ml.). The mixture was refluxed for 20 hours, cooled, diluted with water, and extracted with chloroform. The extract was washed with 2 N sodium hydroxide and water, dried and evaporated to dryness. Recrystallisation of the residue from ethanol or a chloroform-ether mixture gave N-acetyl-l-p-methylaminophenoxy-S-phthalimidopentane, M. P. 83-85 C.

A mixture of N-acetyl-1-p-methylaminophenoxy-5- phthalimidopentane (63.2 g.), 60% hydrazine hydrate (20.8 ml.) and ethanol (150 ml.) was refluxed for 1 hour, then evaporated to dryness. The residue was shaken with warm 2 N sodium hydroxide and chloroform, and the chloroform solution was separated, washed and evaporated to dryness. The residue was stirred with 2 N sodium hydroxide at room temperature whilst benzenesulphonyl chloride (36.75 g.) was slowly added. After 30 minutes, the mixture was extracted with chloroform, the extract was washed with dilute hydrochloric acid and Water, and dried and evaporated to dryness. Crystallisation of the residue from a mixture of toluene and light petroleum (B. P. 40-60 C.) yielded N-acetyl-l-pmethylaminophenoxy 5 benzenesulphonamidopentane, M. P. 109-111 C.

A mixture of N-acetyl-1-p-methylaminophenoxy-5- benzenesulphonamidopentane (65.0 g.), 2 N-hydrochloric acid (91 ml.) and acetic acid (91 ml.) was refluxed for 48 hours, evaporated to dryness in vacuo and cooled. The residue was dissolved in hot water, filtered through Hyflo Supercel (regd. trademark) cooled and made alkaline with 2 N sodium hydroxide. The solid product was filtered and recrystallized from ethanol, giving l-pmethylaminophenoxy 5 benzenesulphonamidopentane, M. P. 85-85" C.

Example V A mixture of 1-p-methylaminophenoxy-5-benzenesulphonamidopentane 11.1 g.), calcium carbonate (5.6 g.), ethylene chlorohydrin (6 ml.) and water (20 ml.) was stirred and refluxed for 20 hours, then cooled, shaken with chloroform and filtered through Hyflo Supercel (regd. trademark). The chloroform solution was separated, dried and evaporated to dryness, and the residue was crystallized from a benzene-light petroleum (B. P. -60 C.) mixture, giving l-p-[N-(2-hydroxyethyl)-N- methylarninophenoxy] S-benzenesulphonamidopentane, M. P. 76-78 C.

Example VI wherein R and R are each selected from the class consisting of hydrogen, alkyl groups containing 1-2 carbon atoms and hydroxyalkyl groups containing 1-2 carbon atoms, n is an integer from 5 to 9 and R is a group selected from the class consisting of methanesulphonamido, benzenesulphonamido and o-sulphobenzimido groups.

2. The compound N-(S-p-aminophenoxypentyl)saccharine.

3. The compound 1-p-aminophenoxy-S-methanesulphonamidopentane.

4. The compound l-p-aminophenoxy-5-benzenesulphonamidopentane.

5. The compound l-p-aminophenoxy-8-benzenesul phonamidooctane.

6. The compound 1-p-dimethylaminophenoxy-S-benzenesulphonamidopentane.

No references cited. 

1. A COMPOUND OF THE GENERAL FORMULA: 